Process for producing 1-substituted benzodiazepine derivatives

ABSTRACT

1-ALKYL-SUBSTITUTED-1,4-BENZODIAZEPINE OR 1,4-BENZODIAZEPIN-2-ONE DERIVATIVE IS PREPARED BY ALKYLATING CORRESPONDING 1-UNSUBSTITUTED-DERIVATIVE WITH CORRESPONDING ALKYL HALIDE OR DIALKYL SULFATE IN THE PRESENCE OF A HYDROCARBONLITHIUM COMPOUND. ACCORDING TO THE PROCESS, THERE ARE PREPARED SUCH VALUABLE COMPOUNDS AS CENTRAL NERVOUSCONTROLLING AGENTS AS 1-CYCLOPROPYLMETHYL-5-PHENYL-7CHLORO - 2,3-DIHYDRO-1H-1,4-BENZODIAZEPINE, 1-METHYL-5PHENYL - 7 - CHLORO-2,3-DIHYDRO-1H-1,4-BENZODIAZEPINE, 1METHYL-5-PHENYL-7-CHLORO-1,3-DIHYRO - 2H - 1,4-BENZODIAZEPIN-2 - ONE AND 1 - CYCLOPROPYLMETHYL - 5 - (O-FLUOROPHENYL)-7-CHLORO-1,3-DIHYDRO - 2H - 1,4-BENZODIAZEPIN-2ONE.

United States Patent 3,832,344 PROCESS FOR PRODUCING l-SUBSTITUTEDBENZODIAZEPINE DERIVATIVES Tadashi Okamoto, Ashiya, Takeshi Akase,Nishinomiya, Takahiro Izumi, Takarazuka, Mitsuhiro Akatsu, Ikeda,Yoshiharu Knme and Shigeho Inaba, Takarazuka, and I-Iisao Yamamoto,Nishinomiya, Japan, assignors to Sumitomo Chemical Company, Limited,Osaka, Japan No Drawing. Filed Oct. 15, 1971, Ser. No. 189,754 Claimspriority, application Japan, Oct. 17, 1970, 45/91,:354; Nov. 7, 1070,45/98,046, 45/98,048; Dec. 25, 1970, 45/129,009

Int. Cl. C07d 53/06 US. Cl. 260-239 BD 4 Claims ABSTRACT OF THEDISCLOSURE This invention relates to a novel process for preparingl-substituted-1,4-benzodiazepine derivatives and salts thereof. Moreparticularly, the present invention relates to a novel process forpreparing a 1-substituted-l,4- benzodiazepine derivative represented bythe general formula (I).

Rn (D wherein A represents a carbonyl or a methylene (CH group; X and Yrepresent individually a hydrogen atom, halogen atom, trifluoromethyl orlower alkyl group; R represents a hydrogen atom, a halogen atom, atrifiuoromethyl or nitro group; R represents a hydrogen atom, a loweralkyl, cycloalkyl, phthalirnido, lower alkenyl, acyloxy, lower alkoxy,cyano, or trihalomethyl group, or a group of the formula -N or CON(where R, and R represent individually a hydrogen atom, a lower alkyl oraralkyl group; or R and R may form 'With the adjacent nitrogen atom afiveor six-membered heterocylic ring which may have any substituent andmay further contain additional hetero atoms in the ring); and

3,832,344 Patented Aug. 27, 1974 n is an integer of 1 to 4; and a saltof the said benzodiazepine derivative.

In l-substituted-1,4-benzodiazepine derivatives represented by theabove-mentioned general formula (I), the term halogen includes chlorine,bromine, iodine and fluorine. The expression alkyl means straight chainas well as branched chain alkyls; examples of lower alkyl includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butylgroups; examples of lower alkenyl include, for example, vinyl, propenyl,isopropenyl, butenyl and the like; examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl; lower alkoxy"includes, for example, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxyand tertiary butoxy; and trihalomethyl groups are, for example,trichloromethyl and trifiuoromethyl groups. The alkylene grouprepresented by C,,H means straight chain as well as branched chainalkylene groups, including methylene ethylene, l-rnethylethylene,Z-methylethylene, trimethylene, l-methyletrirnethylene, and2-methyltrimethylene groups. In the case where R and R forms with the nitrogen atom a heterocyclic ring, the said heterocyclic group is, forexample, pyrrolidino, piperidino, morpholino or piperazino group orsubstituted derivatives thereof. Suitable substituents include loweralkyl, phenyl, halogen-, lower alkylor lower alkoxy-substituted phenyl,alkoxyalkyl, alkenyloxyalkyl, carbamoyl, cyano, and acyloxyalkyl groups.

This invention relates to a process for preparing alsubstituted-1,4-benzodiazepine derivative represented by theaforementioned general formula (I) by reacting a 1-unsubstituted-1,4-benzodiazepine derivative represented by the generalformula (II),

wherein A, X, Y, and R have the same meanings as defined above, with areactive ester of a compound represented by the general formula (III),

wherein R has the same meaning as defined above, in the presence of analkyllithium or an aryllithium.

The l-substituted-1,4 benzodiazepine derivatives represented by theafore-mentioned general formula (I), including novel compounds, haveprominent effects as anticonvulsants, sedatives, muscle relaxants, orhypnotics, and are very important as medicines. This invention is toprovide an improved process for preparing such valuable compounds in anindustrially advantageous manner.

As is known, the l-substituted-l,4-benzodiazepine dcrivativesrepresented by the afore-mentioned general formula (I) could be preparedby alkylation of l-unsubstituted 1,4 benzodiazepine derivatives, withsodium methoxide or sodium hydride and an alkyl halide [Journal ofOrganic Chemistry, 28, 2456 (1963); Journal of Medicinal Chemistry, 8,815 (1965); and British Patent Specification No. 1,148,227]. However,these preparation methods are extremely unsatisfactory from commercialpoint of view, since they produce impure products and the objectiveproducts of the formula (I) are obtained only in low yields. For thepurification of the impure products, there is required a troublesomeprocedure such as chromatography or other complicated method.

Now, in accordance with the present invention, it has been found thatthe desired l-substituted-1,4-benzodiazepine derivatives represented bythe aforementioned general formula (I) can be obtained in good yield anda high degree of purity.

in practising this invention, l-substituted-I,4-benzodia-zepinederivatives of the aforementioned general formula (I) are produced bycontacting a l-unsubstituted- 1,4-benzodiazepine derivative of thegeneral formula (II) with 'an organolithium compound to form aN-l-lithium salt and then reacting the resulting lithium salt with areactive ester of a compound of the general formula (III). Theorganolithium compounds used as metalating agents include alkyllithiumsuch as butyllithium, and aryllithium such as phenyllithium. Thesuitable reactive esters are, in particular, hydrohalic acid esters suchas the chlorides, bromides and iodides, also arylsulfonic acid esterssuch as p-toluene sulfonic acid ester and also sulfuric acid esters suchas dimethyl sulfate and diethylsulfate. The reaction is carried out inthe presence of a solvent or solvent mixture. Suitable solvents includeether, tetrahydrofuran, dioxane, benzene, toluene, xylene and the like.The reaction proceeds at a room temperature but the temperature may belower or higher, for example, 50 to 150 C. It is preferable to carry outthe reaction under an inert atmosphere, such as nitrogen or argon or thelike.

The 1-substituted-benzodiazepine derivative obtained by theaforementioned process may be isolated as an acid addition salt bytreatment with a mineral acid such as, for example, hydrochloric acid,sulfuric acid, nitric acid, or phosphoric acid, or with an organic acidsuch as acetic acid, citric acid, tartaric acid, succinic acid, maleicacid, fumaric acid, palmitic acid, or the like.

By the process of this invention, the followingl-substituted-1,4-benzodiazepine derivatives are obtained in goodyields.

1-Methy1-5-pheny1-7-chloro-2,3 -dihydro-1H-1,4

benzodiazepine 1-Ethyl-5-phenyl-7-chloro-2, 3 -dihydro-lH-1,4-

benzodiazepine 1-Cyclopropylmethyl-5-phenyl-7-chloro-2, 3-dihydro-1'H1,4-benzodiazepine l-Methyl-S o-chlorophenyl -7-chloro2,3-dihydro-1H- 1,4-benzodiazepine 1-Methy1-5-( o-fluorophenyl)-7-chloro-2,3 -dihydro- 1'H-1,4-benzodiazepine1-Methyl-5-phenyl-7-trifluoromethyl-2, 3-dihydro- 1H-1,4-benzodiazepine1-Cyclopropylmethyl-5-phenyl-7-trifluoromethyl-Z, 3

dihydro-1H-1,4-benzodiazepine 1-Diethylaminoethyl-5-phenyl-7-chloro-2,3-dihydro- 1H-1,4-benzodiazepine l-Diethylaminoethyl-S- o-fluorophenyl-7-chloro-2, 3

dihydro-1H-1,4-benzodiazepine 1-Dimethylaminopropyl-5-phenyl-7-chloro-2,3-dihydro- 1H-1,4-benzodiazepine 1-Phthalimidoethyl-5-phenyl-7-chloro-2,3-dihydr0- 1H-1,4-benzodiazepine 1-Phthalimidoethyl-5- (o-chlorophenyl)-7-chloro-2,3-

dihydro-1H-1,4-benzodiazepine1-Allyl-5-phenyl-7'chloro-1,3-dihydro-2H-1,4-

benzodiazepin-Z-one 1a trans-Butenyl) --phenyl-7-chloro- 1, 3-dihydro-2H- 1,4-benzodiazepin-2-one1Methallyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-

benzodiazepin-Z-one 1- 3- Methoxyethyl -5-phenyl-7-chloro- 1,3-dihydro-2H- 1,4-benzodiazepin-2-one 1- (fi-Methoxyethyl)-5-(o-fluorophenyl)-7-chloro-1,3-

dihydro-ZH-1,4-benzodiazepin-2-one 1- (fi-Ethoxyethyl)-5-phenyl-7-chloro-1, 3-dihydro-2H- 1,4-benzodiazepin-2-one 1-B-Ethoxyethyl) -5- (o-chlorophenyl) -7-chlor0-1, 3-

dihydro-2H-l,4-benz0diazepin-2-one 1- (B-Ethoxyethyl) -5- (o-tolyl-7-chloro-1, 3-dihydro-2H- 1,4-benzodiazepin-2-onel-Methyl-S-(o-fluorophenyl)-7-chloro-1,3-dihydro2H-1,4-benzodiazepin-2-one1-Cyanomethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-

benzodiazepin-Z-one 1 2',2,2-Trifluoroethyl)-5-phenyl-7-chloro-1,3-dihydro- 2H-1,4-benzodiazepin-2-one 1-N,N-Dimethylcarbamoylmethyl) -5-(o-fluoropheny1)- 7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one 1- (fl-Diethylaminoethyl) -5-(o-fluorophenyl -7- chloro- 1,3-dihydro-2H-1,4-benzodiazepin-2-one 1-fl-Acetoxyethyl) -5-phenyl-7-chloro-1,3-hydro-2H-1,4-

benzodiazepin-Z-one1-(pi-Actoxyethyl)-5-(o-fluoropheny1)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one1- (/8-Diethylaminoethyl) -5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one 1- (fl-Ethoxypropyl -5-phenyl-7-chloro-1,3-dihydro- 2H-1,4-benzodiazepin-2-one 1- (fi-Methoxypropyl-5-phenyl-7-bromo-1,3-dihydro- 2H-1,4-benzodiazepin-2-one 1-(B-Methoxyethyl-5-pheny1-7-trifluoromethyl1,3-dihydro-2H-1,4-benzodiaZepin-2-one 1-fi-Methoxyethyl -5 (0,0 -difluorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one 1- fl-Methoxyethyl-5-phenyl-7-nitr0- 1,3 -dihydr0-2H- 1,4-benzodiazepin-2-one1-Cyclopropylmethy1-5-phenyl- 1,3-dihydro-2H- 1 ,4-

benzodiazepin-Z-one I-Cyclopropylmethyl-S- (o-fluorophenyl-7-chloro-1,3-

dihydro-ZH-1,4-benzodiazepin-2-one 1-Cyclobutylmethyl-5-phenyl-7-chloro- 1, 3-dihydro-2H-1,4-benzodiazepin-2-one 1- B-Morpholinoethyl -5-phenyl-7-ch1oro-1,3-dihydro- 2H-1,4-benzodiazepin-2-one1-Cyclopropylmethyl-S-phenyl-7-chl0ro-1,3 -dihydro-2H-1,4-benzodiazepin-2-one 1- (B-Methoxypropyl-5-phenyl-7-chloro-1,3-dihydro- 2H-1,4-benzodiazepin-2-one 1-(fl-Ethoxypropyl -5- (o-fluorophenyl -7-chloro- 1 ,3-

dihydro-ZH-1,4-benzodiazepin-2-one.

A compound of the aforementioned general formula (II), wherein A is amethylene (-CH that is, a 1- unsubstituted 1,4 benzodiazepine derivativerepresented by the general formula (II),

wherein R X and Y have the same meanings as defined above, may beprepared by hydrolyzing a 2,3-diox0piperazinobenzophenone derivativerepresented by the general formula (IV),

wherein R X and Y have the same meanings as defined above.

The 2,3-dioxopiperazinobenzophenone derivatives represented by theaforementioned general formula (IV) is heated in a solvent in thepresence of a hydrolyzing agent to form1-unsubstituted-1,4-benzodiazepine derivative represented by the generalformula (II). Suitable solvents are, for example, water, methanol,ethanol and propanol, and a mixture thereof. Hydrolyzing agents includesodium hydroxide, potassium hydroxide, lithium hydroxide, sodiumcarbonate, and potassium carbonate and the like. The reaction isgenerally conducted at elevated temperatures, preferably at the boilingtemperature of the solvent employed.

The 2,3-dioxopiperazinobenzophenone derivatives represented by the abovegeneral formula (IV) are novel compounds and may be prepared in goodyields by, for example, oxidizing piperazino [1,2-a] indole derivativesrepresented by the general formula (V),

CH; wherein R X and Y have the same meanings as defined above.

The invention is further illustrated by the following examples ofpreferred embodiments thereof, which are presented for the purpose ofillustration and are not intended to limit the scope of the invention.

EXAMPLE 1 A mixture of g. of 2-(2",3" dioxopiperazino) 5-chlorobenzophenone and 240 g. of 95% ethanol is heated under reflux Withstirring. To the mixture is added a solution of 12 g. of sodiumhydroxide in g. of water under reflux with stirring and the resultingmixture is stirred under reflux for one hour. To the reaction mixture isadded 300 g. of water, and heated under reflux for 20 hours withstirring. Then, the reaction mixture is concentrated to remove most ofethanol. The residue is crystallized. Upon adding 300 g. of water andstanding overnight at 5-10 C. The crystals are collected by filtrationand Washed with 100 g. of water to give 15 g. of crude5-phenyl-7-chloro-2,3-dihydro 1H 1,4 benzodiazepine. The crude crystalsare recrystallized from aqueous 70% ethanol to yield 13.2 g. of5-phenyl-7-chl0ro-2,3-dihydrolH-1,4-benzodiazepine having a meltingpoint of 172- 173 C. An additional 0.9 gram of crystals having a meltingpoint of 172-173 C. is obtained from the filtrate as a second crop.

EXAMPLE 2 To a solution of 25.6 g. of potassium hydroxide in 288 ml. ofWater is added 30 g. of 2- (2,*3"-dioxopiperazino)- S-chlorobenzophenoneand 115 g. of methanol below C. The mixture is heated under reflux for16 hours. The reaction mixture is concentrated and cooled. Theprecipitate is collected by filteration, washed with water and suspendedin 1.9 l. of Water, and 160 g. of 10% sulfuric acid is added dropwise tothe mixture below 5 C. to give a solution. The solution is filtered andthe filtrate is basified with 5% aqueous sodium hydroxide solution andstirred for 30 minutes. The precipitate is collected by filteration,washed with water and dried to give 21.05 g. (89.8%) of5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine, melting at 17017lC.

EXAMPLE 3 In a manner similar to that in Examples 1 and 2 but replacing2-(2",3 dioxopiperazino) 5 chlorobenzo- 6 phenone by2-(2",3"-dioxopiperazino) -5-chloro-2-fluorobenzophenone, there isobtained 5- (o fluorophenyl)-7 chloro-2,3-dihydro-1H 1,4 benzodiazepinemelting at l6l163 C.

EXAMPLE 4 In a manner similar to that in Examples 1 and 2, but replacing2-(2,3" dioxopiperazino) 5 chlorobenzophenone by2-(2",3"-dioxopiperazino) 2',5 dichlorobenzophenone, there is obtained5-(o-chlorophenyl)-7- chloro-2,3-dihydro-1H 1,4 benzodiazepine, meltingat 175 177 C.

EXAMPLE 5 In a manner similar to Examples 1 and 2, but replacing2-(2",'3"-dioxopiperazino) 5 ch'lorobenzophenone by 2 (2,3"dioxopiperazino) 5 trifluoromethylbenzophenone, there is obtained5-phenyl-7-trifluoromethyl-2,3- dihydro-lH-l,4-benzodiazepine.

EXAMPLE 6 A solution of 8 g. of bromobenzene in 20 ml. of anhydrousether is added dropwise to a mixture of 0.7 g. of lithium and 20 ml. ofanhydrous ether under a nitrogen atmosphere. After completion of theaddition, the mixture is stirred for 20 minutes at room temperature, andthen the resulting mixture is added to a solution of 9 g. of5-phenyl-7-chloro-2,3-dihydro-1H-1,4 benzodiazepine in ml. of anhydroustetrahydrofuran at 15 C. under an inert nitrogen atmosphere. After theaddition is over the mixture is stirred for 20 minutes at roomtemperature. The resulting mixture is cooled to 10 C., and a solution of7 g. of methyl iodide in 20 ml. of ether is added dropwise thereto.After stirring for 4 hours at 20 C., the reaction mixture isconcentrated to dryness under reduced pressure. To the residue, areadded a 2-3% aqueous sodium chloride solution and 300 ml. of benzene andthe resultant solution is mixed. The benzene layer is separated, washedtwice with an aqueous sodium chloride solution, and then extracted twicewith m1. of 1N-hydro chloric acid. The hydrochloric acid solution isneutralized with aqueous ammonia, and extracted three times with 150 ml.of benzene. The benzene layer is washed with an aqueous sodium chloridesolution, and dried over anhydrous sodium sulfate. The benzene solutionis filtered through a pad, of silica gel (9 g., in 1 cm. thickness,100-200 mesh). The silica gel pad is washed with 200 ml. of ethylacetate. The filtrate and the washings are combined. The combinedsolution is concentrated to dryness under reduced pressure to give 9.1g. of nearly pure l-methy1-5-phenyl-7-chloro-2,3-dihydro 1H 1,4benzodiazepine. On recrystallization from hexane, there are obtained 7.7g. of crystals of 1-methyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine, melting at 9697 C.

EXAMPLE 7 A solution of '8 g. of bromobenzene in 20 ml. of anhydrousether is added dropwise to a mixture of 0.7 g. of lithium (wire cut intosmall pieces) and 20 ml. of anhydrous ether at 20-30 C. under a nitrogenatmosphere. After addition is over, the mixture is stirred at roomtemperature for 20 minutes, and then reaction mixture is added dropwiseto a solution of 9 g. of 5-phenyl-7- chloro-2,3-dihydro-lH-l,4benzodiazepine in 100 ml. of anhydrous tetrahydrofuran at 15 C. under anitrogen atmosphere. The mixture is stirred at room temperature for 20minutes and then cooled to 10 C. To the mixture is added dropwise asolution of 7 g. of methyl iodide. The mixture is stirred at 20 C. for 4hours. The reaction mixture is concentrated to dryness under reducedpressure. The residue is dissolved in 300 ml. of benzene and washed withaqueous sodium chloride solution, and extracted with hydrochloric acid.The hydrochloric acid solution is neutralized with aqueous sodiumhydroxide solution and extracted with benzene. The benzene solution iswashed with aqueous sodium chloride solution, and concentrated todryness under reduced pressure to give 9.4 g. of pale yellow oil. Theoily residue is crystallized from n-hexane to give 7.9 g. ofl-methyl-S-phenyl 7 chloro 2,3 dihydro-lH-l,4benzodiazepine, melting at9597 C.

From the filtrate, there is obtained 0.5 g. of additional crystals asthe second crops.

EXAMPLE 8 A mixture of 21 g. of 16.6% ether-benzene solution ofphenyllithium and 20 ml. of toluene is added dropwise to a stirredsuspension of 10 g. of 5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine in a mixture of 120 ml. of toluene and 10ml. of tetrahydrofuran at 5 C. After stirring for 30 minutes, 8.3 g. ofmethyl iodide in 10 ml. of toluene is added to the mixture below C., andthe mixture was stirred at 5l0 C. for 3 hours. The reaction mixture isdiluted with 100 ml. of ice-water. The organic layer is separated,washed with aqueous sodium chloride solution and extracted with 5%sulfuric acid. The sulfuric acid layer is basified with 5% aqueoussodium hydroxide solution and extracted with toluene. The tolueneextract is washed successively with Water, 5% aqueous sodium bisulfitesolution and then aqueous sodium chloride solution, dried over anhydroussodium sulfate, and concentrated to dryness. The residue is crystallizedfrom n-hexane to give 8.5 g. (80.5%) of l-methyl- 5 phenyl7-chloro-2,3-dihydro-lH-1,4-benzodiazepine, melting at 102103 C.

EXAMPLE 9 In a manner similar to those described in Examples 6, 7 and 8,there is obtained 1-cyclopropylmethyl-S-phenyl- 7 chloro 2,3dihydro-1H-1,4-benzodiazepine, having a melting point of 78-80 C. afterrecrystallization from isopropyl ether.

EXAMPLE 10 In a manner similar to those described in Examples 6, 7 and8, but using5-(o-chlorophenyl)-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine in placeof 5-phenyl-7- chloro 2,3 dihydro-lH-1,4-benzodiazepine, there isobtained 1-methyl-5- o-chlorophenyl) -7-chloro-2,3dihydro-1H-l,4-benzodiazepine was obtained, which has a melting point of 9394.5C. after recrystallization from isopropyl ether.

Similarly, the following compounds are prepared.

1 Methyl 5 (o-fluorophenyl)-7-chloro-2,3-dihydro- 1H-l,4-benzodiazepine,m.p. 9l-92.5 C.; l-cyclopropylmethyl5-(o-chlorophenyl)-7-chloro-2,3-dihydro1H-1,4- benzodiazepine, m.p. 8889C.

EXAMPLE 11 A solution of 8 g. of bromobenzene in 20 ml. of ether isadded dropwise to a mixture of 0.7 g. of lithium in fine pieces and 20ml. of anhydrous ether, under nitrogen. The resulting solution is addeddropwise to a solution of 9 g. of 5 phenyl 7-chloro2,3-dihydro-lH-l,4-benzodiazepine in 90 m1. of tetrahydrofuran at 15 C.under nitrogen. After addition, the mixture is stirred for minutes atroom temperature, and then cooled to 10 C. To the mixture is addeddropwise a solution of 6.7 g. of B-diethylaminoethyl chloride in 10 ml.of ether over a period of 5 minutes. The mixture is stirred for 4 hoursat 20 C. The reaction mixture is concentrated to dryness under reducedpressure. The residue is dissolved in 200 ml. of benzene, washed with200 ml. of water followed by an aqueous sodium chloride solution, andthen extracted twice with 200 ml. of lN-hydrochloric acid. Thehydrochloric acid solution is neutralized with an aqueous sodiumhydroxide solution, and then extracted with benmm and washed with waterfollowed by an aqueous dium chloride solution and dried over sodiumsulfate, and the solvent is removed. The residue, is recrystallized fromhexane to give 8.8 g. of l-(fi-diethylaminoethyl)-5-phenyl-7-chloro-2,3dihydro-1H-1,4-benzodiazepine as an oil. The freebase is dissolved in ether, and gaseous hydrogen chloride is introducedtherein to precipitate its dihydrochloride. The precipitated crystals iscollected by filtration, washed with ether, and then recrystallized fromisopropanol to give I-(B-diethylaminoethyl)-5-phenyl-7- chloro 2,3dihydro-lH-1,4-benzodiazepine dihydrochloride as yellow crystals,melting at 234236 C.

EXAMPLE 12 To a solution of 9 g. of 5-phenyl-7-chloro-2,3-dihydro-1H-l,4-benzodiazepine in ml. of tetrahydrofuran, is added dropwise asolution of phenyllithium in ether prepared in the same manner as inExample 11 under a nitrogen atmosphere. The mixture is stirred at 20 C.for 20 minutes and a solution of 12.5 g. of N-(Z-bromoethyl) phthalimidein 30 ml. of tetrahydrofuran is added dropwise thereto at 16 C. Thereaction mixture is stirred at 20 C. for 4 hours, and then the solventis removed under reduced pressure. The residue is dissolved in benzeneand washed with water followed by an aqueous sodium chloride solution,and extracted with IN-hydrochloric acid. The hydrochloric acid extractlayer is neutralized with an aqueous sodium hydroxide solution andextracted with benzene. The benzene layer is washed with water, driedover sodium sulfate, and the benzene is removed. The oily residue (16g.) is crystallized from ml. of hot cyclohexane to give 13.5 g. of1-(2'-phthalimidoethyl)5-phenyl-7-chloro-2,S-dihydro-1H-1,4-benzodiazepine which isrecrystallized from cyclohexane-isopropyl alcohol (2:1), m.p. 176 C.

EXAMPLE 13 A solution of phenyllithium in ether prepared from 0.7 g. oflithium and 8 g. of bromobenzene is added dropwise to a solution of 8 g.of 5-phenyl-7-chloro-1,3- dihydro-2H-1,4-benzodiazepin-2-one in 100 ml.of tetrahydrofuran at 10l5 C. under nitrogen atmosphere. After additionis over, the mixture is stirred at 10 C. for 30 minutes. To the reactionmixture, is added dropwise 7 g. of methyl iodide, and stirred at 20-23C. for wise 7 g. of methyl iodide, and stirred at 20-23 C. for 6 hours.Then, the reaction mixture is concentrated under reduced pressure,admixed with water, and extracted with chloroform. The chloroform layeris washed with an aqueous sodium chloride solution and dried over sodiumsulfate, and the solvent is removed under reduced pressure. The residueis recrystallized from isopropanol to give 7.6 g. of1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H- 1,4-benzodiazepin-2-onehaving a melting point of 131- 133 C.

Similarly, the following compounds are prepared.

1-Cyclopropylmethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 143 145 C.

l-Cyclopropylmethyl-S-(o-fluorophenyl)-7-chloro-1,3- dihydro 2H 1,4benzodiazepin 2 one, m.p. 8688 C.

1-(fl-DiethylaminoethyD-S- (o-fluorophenyl)-7-chloro-1,3

dihydro-2H-1,4-benzodiazepin-2-one, m.p. 8283 C.

1- (,B-Methoxyethyl) -5-phenyl-7-chloro-1,3-dihydro-2H-1,4benzodiazepin-2-one, m.p. 108 109 C.

What is claimed is:

1. A process for producing I-substituted benzodiazepine derivativesrepresented by the formula,

wherein A represents a group of the formula CH X and Y representindividually a hydrogen atom, a halogen atom, a trifluoromethyl or a C-C alkyl group; R represents a hydrogen atom, a halogen atom, atrifluoromethyl or nitro group, R represents a hydrogen atom, a C -Calkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phthalimido, C-C alkenyl, C -C alkanoyloxy, C -C alkoxy, cyano or trifluoromethylgroup or a group of the formula -CON or --N where R and R representindividually a C -C alkyl, benzyl, or phenethyl group; or R and R mayform with the adjacent nitrogen atom a pyrrolidino, piperidino,piperazino or morpholino group; and n is an integer from 1 to 4; or saltthereof, which comprises treating a l-unsubstituted-1,4-benzodiazepinederivative represented by the formula,

wherein R and n have the same meanings as defined above with an acidselected from the group consisting of hydrohalic acid, arylsulfonic acidand sulfuric acid.

2. A processing according to claim 1 wherein a 1-substituted-1,4-benzodlazepine derivative represented by the formula,

wherein X is hydrogen atom; Y is hydrogen or halogen atom ortrifluoromethyl group; R is hydrogen atom or halogen atom ortrifiuoromethyl group and R is the grouping C,,H R (where R is di-C -Calkylamino or phthalimido group; n is an integer of 1 to 3) is preparedby treating an l-unsubstituted-1,4-benzodiazepine derivative representedby the formula,

N-CH: H (II-a) wherein X, Y and R are the same as defined above, with anorganolithium compound selected from the consisting of butyllithium andphenyllithium in the presence of a solvent or solvent mixture at atemperature ranging from 50 C. to C. to form the N-lithium salt and thenreacting the resulting lithium salt with a reactive ester, said esterformed by reacting a compound represented by the formula,

R OH

wherein R is the same as defined above with an acid selected from thegroup consisting of hydrohalic acid, arylsulfonic acid and sulfuricacid.

3. A process according to claim 1, wherein A is X and Y are hydrogen; Ris chlorine; R is hydrogen; n is 1; said organolithium compound is thereaction product or bromobenzeue and lithium and said reactive ester ismethyl iodide.

4. A process according to claim 1, wherein said reactive ester is acompound of the formula,

R C -H Z (III-a) wherein R and n are the same as defined in claim 1 andZ is a halogen atom.

References Cited UNITED STATES PATENTS 3,299,053 1/1967 Archer et a1.260239.3 3,391,138 7/1968 Archer et a1. 260239.3

JOSEPH A. NARCAVAGE, Primary Examiner U.S. Cl. X.R.

260-2393 D, 268 DK, 999

